Richardson, Alicia
(2025)
Part A – AI-Designed Protein Binders Tackle a Century-Old
Challenge: Tc24 as a Universal Vaccine Antigen for Chagas
Disease
Part B – Expression, Purification and Biophysical Characterisation
of de novo binders designed against the Flagellar Calcium
Binding Protein, Tc24.
MRes thesis, University of Nottingham.
Abstract
Part A – Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains one of the most
neglected tropical diseases, disproportionately affecting low-income, rural populations across
Latin America. Despite over a century since its discovery, there is still no effective vaccine and
therapies currently rely on the usage of nifurtimox and benznidazole, which have been linked
to severe side effects. This review explores the multifaceted challenges of developing both a
therapeutic and prophylactic treatment for Chagas disease. Particular attention is given to the
flagellar calcium-binding protein Tc24, a highly conserved, immunogen expressed across all
morphological stages of T. cruzi.
In parallel, this review examines how artificial intelligence (AI) and deep learning (DL)
platforms are revolutionising structural prediction and binder design. These technologies
enable the in silico development of both high-affinity and target-specific binders at low cost.
In summary, this review proposes the integration of conserved antigen targets, with AI-guided
binder design presents a novel framework for overcoming current barriers in vaccine
development, offering renewed hope for the prevention and management of Chagas disease.
Part B – Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains one of the most
neglected tropical diseases, disproportionately effecting affecting socioeconomically
impoverished regions across Latin America. Despite over a century of research since its
discovery, there is still no effective vaccine, and current therapies rely on the usage of
nifurtimox and benznidazole which have been linked to severe side effects. Tc24, a highly
conserved flagellar calcium binding protein remains an attractive vaccine candidate.
This study experimentally evaluated six RFdiffusion designed binders against Tc24. Although
no functional binders were identified, these results highlight limitations of current binder
design pipelines and emphasise the need for incorporating solubility parameters in future Tc24
binder development.
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